Project Summary Very fragile yet highly structured, the lung is assaulted with potential pathogens, allergens, and irritants with every breath. Yearly epidemics of influenza virus are a significant source of morbidity and mortality, presenting a major health obstacle with high economic burden for the United States and the world. Notably, the short incubation period, high infection rate, and rapid transmission of the influenza virus uniquely complicates the care of patients with pulmonary co-morbidities. However, the presence of effector memory CD8 T cells in the lungs can quickly control the local spread of a pathogen while mitigating an undesired and potentially deleterious wide-spread inflammatory response in the lungs. Key findings from human and animal model studies denoted that the protective efficacy of airway-resident memory CD8 T (TARM) cells directly correlates with the number of memory CD8 T cells present in the lung airways at the time of influenza challenge; as the number of TARM cells declined, so did protection from influenza challenge. Yet, it is unknown how TARM cells are maintained at the site of infection, the lung airways, where they are uniquely positioned to rapidly respond to an influenza infection. The first step in the process is elucidating the manner by which these memory CD8 T cells enter the lung from the general circulation. It is accepted that a chemokine receptor and adhesion molecule pair is necessary for trafficking of resident memory CD8 T (TRM) cell subsets to specific peripheral tissues. While the adhesion molecule has been identified, the chemokine receptor necessary for steady-state recruitment of memory CD8 T cells to the lungs has not. Identification of this specific chemokine receptor and elucidation of the mechanisms that regulate its expression are the basis of this proposal. The goal of the proposed project is to define the role of the chemokine receptor CXCR6 in steady-state trafficking of influenza- specific memory CD8 T cells to the lung airways and to identify the factors that regulate CXCR6 expression. In addition to gaining insight to the role of CXCR6, it is hoped that these studies will create a platform to advance the field of prophylactic cell-mediated vaccines against respiratory pathogens and to develop novel therapeutic agents that promote pathogen-specific T cell recruitment to the lung airways; in this manner, such agents could enhance protective immunity to respiratory pathogens. Such advances would strengthen preventative care methods to impart a higher quality of life for patients. The proposed research project will serve as a framework for the applicant's training plan, which is specifically designed to integrate basic science research in pulmonary mucosal immunology with the applicant's career goal of becoming an independent physician scientist whose research focus will be viral mucosal immunology.